Bmal1 regulates circadian expression of cytochrome P450 3a11 and drug metabolism in mice

• Published in: Communications biology 2019-10, Vol.2 (1), p.378, Article 378
• Main Authors: Lin, Yanke, Wang, Shuai, Zhou, Ziyue, Guo, Lianxia, Yu, Fangjun, Wu, Baojian
• Format: Article
• Language: English
• Subjects: 13; 13/1; 13/109; 38; 38/1; 38/39; 631/154/570; 631/337; 631/45; 631/80; Aconitine - metabolism; Aconitine - toxicity; Animals; ARNTL Transcription Factors - deficiency; ARNTL Transcription Factors - genetics; ARNTL Transcription Factors - metabolism; Biology; Biomedical and Life Sciences; BMAL1 protein; Cell Line; Circadian Clocks - genetics; Circadian rhythm; Circadian Rhythm - genetics; Circadian Rhythm - physiology; Circadian rhythms; Cytochrome P-450 CYP3A - genetics; Cytochrome P-450 CYP3A - metabolism; Cytochrome P450; Detoxification; Diterpenes - metabolism; Diterpenes - toxicity; DNA-Binding Proteins - genetics; Drug metabolism; Epoxy Compounds - metabolism; Epoxy Compounds - toxicity; Gene Expression Regulation, Enzymologic; Gene regulation; Hepatocyte Nuclear Factor 4 - genetics; Humans; Inactivation, Metabolic; Life Sciences; Male; Membrane Proteins - genetics; Membrane Proteins - metabolism; Metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Pharmaceutical Preparations - metabolism; Phenanthrenes - metabolism; Phenanthrenes - toxicity; Promoter Regions, Genetic; Protein deficiency; Protein turnover; RNA, Messenger - genetics; RNA, Messenger - metabolism; Toxicity; Transcription Factors - genetics; Triptolide; Xenobiotics - metabolism; Xenobiotics - toxicity
• ISSN: 2399-3642; 2399-3642
• DOI: 10.1038/s42003-019-0607-z

Metabolism is a major defense mechanism of the body against xenobiotic threats. Here we unravel a critical role of Bmal1 for circadian clock-controlled Cyp3a11 expression and xenobiotic metabolism. Bmal1 deficiency decreases the mRNA, protein and microsomal activity of Cyp3a11, and blunts their circadian rhythms in mice. A screen for Cyp3a11 regulators identifies two circadian genes Dbp and Hnf4α as potential regulatory mediators. Cell-based experiments confirm that Dbp and Hnf4α activate Cyp3a11 transcription by their binding to a D-box and a DR1 element in the Cyp3a11 promoter, respectively. Bmal1 binds to the P1 distal promoter to regulate Hnf4α transcriptionally. Cellular regulation of Cyp3a11 by Bmal1 is Dbp- and Hnf4α-dependent. Bmal1 deficiency sensitizes mice to toxicities of drugs such as aconitine and triptolide (and blunts circadian toxicity rhythmicities) due to elevated drug exposure. In summary, Bmal1 connects circadian clock and Cyp3a11 metabolism, thereby impacting drug detoxification as a function of daily time. Lin, Wang et al. show that a core clock transcription factor Bmal1 regulates the expression of a major drug detoxification enzyme Cyp3a11 and the daily rhythm of drug metabolism through Dbp and Hnf4α. This study suggests that Bmal1 connects circadian clock and Cyp3a11 metabolism to regulate drug detoxification as a function of daily time.